Although poor growth in diabetic and malnourished children is attributed to decreased utilization of nutrients, the mechanism of the defect is not known. Skeletal growth is ascribed to stimulation of growth cartilage by somatomedins, circulating anabolic factors generated in the liver. Our studies suggest that other circulating factors, somatomedin inhibitors, may limit the stimulation of cartilage by somatomedins; bioassay measurements of net somatomedin activity appear to reflect both somatomedins and somatomedin inhibitors. In our animal models, lack of nutrients and/or insulin is associated with reduced net somatomedin activity and poor growth. While alterations in net somatomedin activity might direct utilization of nutrients toward or away from growth, the underlying control processes are not understood. To elucidate the metabolic regulation of somatomedin activity, the following studies are proposed. 1) To determine whether circulating net somatomedin activity is linked closely to metabolic status in man, net somatomedin activity will be measured in diabetics with varying metabolic control and in fasted obese patients given diets of varying nutritional composition. 2) To study the liver as the putative locus of the somatomedin-regulating interactions, new methodology will be used a) to relate extractable hepatic content of somatomedin activity in rats to metabolic status in vivo and b) to relate net formation of somatomedin activity during liver perfusions both to metabolic status of donor animals in vivo and to regulatory hormones added in vitro. 3) To examine the role of somatomedin inhibitors, attempts will be made a) to characterize the inhibitors biologically and biochemically, b) to develop procedures for measuring both somatomedins and somatomedin inhibitors, and c) to use these procedures to study the relationship of somatomedins and inhibitors to each other, to metabolic status, and to growth. These studies should provide improved understanding of the regulation of normal rowth, insight into the pathophysiology of impaired growth, and new concepts for therapy of growth failure in diabetes mellitus and malnutrition.